In order to determine the composition of measuring media, in particular liquids, such as pure liquids, liquid mixtures, emulsions or suspensions, various analytical measuring devices are used in process measuring procedures. An analytical measuring device generally comprises a sensing element which is designed to generate a measuring signal dependent upon at least one analytical measurand, as well as a measurement electronic device, which from the measuring signal, determines a measured value representing the current value of the at least one analytical measurand in the measuring medium. The analytical measurand can, for example, be a concentration or activity of an analyte or a parameter dependent upon a concentration or activity of at least one analyte in the measuring medium. An analyte here means one or more substances contained in and, in particular, dissolved in the measuring medium whose concentration in the measuring medium is to be determined or monitored by the analytical sensor. The analyte can even be present in the measuring medium in an undissolved state, and this frequently requires dissolution to be carried out before measurement of the analytical measurand with the sensing element. The measurement electronic device can at least partially be integrated in a measuring transducer, which has a housing with display and input elements, located immediately at the measurement point.
Analytical measuring devices are used in a variety of areas, for example, for monitoring and controlling processes in pharmaceutical, chemical, biotechnical or biochemical production, and even in processes for water conditioning or sewage purification and also in environmental analysis. When an analytical measuring device is used in a process, the measuring medium will usually be contained in a process vessel. In the field of environmental analysis, the measuring medium can also be an open body of water.
A selection of several analytical measuring devices based on different measuring principles is often available for measuring a specific analytical measurand. Each measuring principle has its own specific advantages and disadvantages.
To measure the concentration of a water ingredient, e.g. of a special ion concentration, automatic analyzers are known, for example, which pretreat a sample of the liquid to be analyzed taken from the process for analysis, e.g. by the addition of reagents, and record a measurand dependent upon the concentration of the water ingredient by means of a sensing element in the pretreated sample. The sample to be analyzed is often pretreated inside the analyzers by adding one or a plurality of reagents, thus provoking a chemical reaction in the sample with the participation of the analyte. The reagents are preferably selected such that the chemical reaction can be demonstrated by means of an optical or electrochemical measuring principle, e.g. by means of a photometric sensing element, a potentiometric or an amperometric sensor, or a conductivity sensor. For example, the chemical reaction can cause a coloration of the sample or an emission of luminescent radiation. The color intensity, which can be determined by means of absorption or extinction measurement or the intensity of the luminescent radiation, is in this case a measure of the analytical measurand to be determined. The absorption or extinction for a wavelength correlating to the coloration of the sample may, for example, be determined by photometric means by feeding electromagnetic radiation, such as visible light, from a radiation source into the liquid sample, and receiving it with a suitable detector after transmission through the liquid sample. The detector generates an electrical measurement signal which depends on the intensity of the radiation received and from which a measured value of the analytical measurand can be derived.
Such analyzers are known, for example, from DE 10 22 822 A1, DE 10 2009 029 305 A1 or DE 10 2011 075 762 A1. On the one hand, they deliver very accurate measured values; on the other hand, a relatively long period of time is needed for a measurement cycle which comprises the taking of the sample, the pretreatment of the sample and the determination of a measured value by means of a photometric measurement of the pretreated sample. Said time period can last between 5 and 120 minutes depending on the analytical measurand to be determined. This type of analytical measuring device may therefore only be used with restrictions for monitoring and/or controlling or regulating very dynamic processes.
On the other hand, so-called in-line measuring devices, in particular electrochemical sensors, such as potentiometric ion-selective electrodes (ISEs) or amperometric sensors, are also known for determining the concentration of water ingredients, such devices reacting in close to real time to fluctuations in the value of the measurand. An in-line measuring device is integrated directly into a process vessel in which the process to be monitored is carried out or which contains a process medium being used in the process, and records the measurand directly in the process medium to be monitored. The taking and pretreatment of a sample from a process can therefore be dispensed with for in-line measuring devices. However, in-line measuring devices often comprise an amperometric, potentiometric, photometric or spectrometric sensing element which has a not insignificant cross-sensitivity to other parameters or measurands, in particular to changes in the water matrix. Measured values that are determined using such measuring devices are, therefore, generally subject to a higher degree of measuring error than the measured values determined by an analyzer. In addition, with several ion-selective electrodes an age-related drift occurs which can be compensated for to a certain extent by regular calibration or adjustment of the ion-selective electrodes.
A very similar problem also exists in the field of biological or biotechnological production processes in which microorganisms or their components are used. In such processes it is important for the measurands related to process control, so-called process control parameters and/or product-quality-related parameters or measurands, to be determined near-contemporaneously with the process by means of an appropriate process measuring technology so as to enable a high level of productivity to be achieved by increasing the yield with minimized production runtimes.
A known system concept of this type of process measuring technology for biotechnological applications is based on the use of spectroscopic in-line measuring devices. In this case, a sensing element designed as an in-line sensor is introduced into the process via a suitable port arranged in the wall of a process vessel, for example, via a standard Ingold port. The in-line sensor is therefore in direct contact with the process. The system components of the sensor located in the process must therefore be sterilizable, that is they should advantageously be stable with respect to CIP or SIP processes (the abbreviation CIP stands for “cleaning in process”, SIP stands for “sterilization in process”) and autoclaving. A spectroscopic sensing element comprises a radiation source that emits electromagnetic measuring radiation which interacts with the process medium and is then measured again by means of a radiation detector of the sensing element. The radiation source and the radiation detector can be located inside the housing of the in-line sensor or inside a unit at a distance from the process or the housing of the sensor, referred to as a spectrometer. In the latter case, the measuring radiation coming from the radiation source is guided along optical fibers from the spectrometer to the sensor housing and the radiation to be measured by the detector is also guided along optical fibers from the sensor housing back to the spectrometer. A distinction can be drawn between UV/Vis, MIR, NIR, and Raman spectroscopy depending on the wavelength range or wave number of the measuring radiation and the type of detection or reception (transmission, reflection, scattering).
The measuring of measured values by means of a spectroscopic in-line measuring device can take place with a rapid rate of measurement and with a short delay between measurement and result which is negligible with respect to process changes. This means that the process can be monitored in close to real time so that the measured values made available by the in-line measuring device can also be used to control or regulate the process.
However, the measurement results obtained using such spectrometric in-line measuring devices only constitute a prediction which can be calculated from the spectroscopic data on the basis of a chemometric model. As a rule, the chemometric model is developed from data determined in the development of the process or from data determined in the past during the implementation of the process. To that end, it is necessary to correlate the spectroscopic data with analytical values of a reference analysis which in most cases does not take place automatically or as part of the process. Quantitative determinations by means of in-line spectroscopy and subsequent chemometric evaluation are known for the measurands glucose content, glutamine content, glutamate content, lactate content, ammonium content, osmolality, viable and total cell density. These types of commercially available systems are offered, for example, by Kaiser Optical Systems Inc. under the product name RAMANRXN2 1000 or by Bayer Technology Services GmbH under the product name SpectroBAY.
Alongside the described disadvantage of a complex data generation or evaluation process and protracted correlation analyses, the adaptability of this system concept to process-specific, process-critical or quality-related measurands is severely restricted. Detection limits and accuracies of the measurands which can be determined from spectrometric data are also inadequate in part. They often go hand in hand with a low measuring accuracy particularly with a low concentration and/or high concentrations of interferents, i.e. a not insignificant cross-sensitivity of the in-line sensing element. This is, for example, of great importance for avoiding stress conditions for accurate nutrient determination (e.g. glucose) with a sufficiently low detection level. Stress conditions can lead to reduced microorganism growth, reduced product expression, undesirable by-product expression and/or to a reduction in product quality. It is, therefore, important for the control of bioprocesses to identify such stress conditions early on and to effect controlled intervention in the process in order to prevent or eliminate them.
As an alternative to in-line measuring devices, automated analyzers which determine one or a plurality of this type of measurands by applying analytical methods are also suitable for determining the above-mentioned process control parameters and/or the specified product-quality-related measurands. Just like the aforementioned analyzers which are suitable for determining water ingredients, the automated analyzers suitable for monitoring bioprocesses comprise means for taking samples from the process, means for pretreating the sample to be analyzed, for example by the addition of reagents, which leads to a change in the sample which can be measured by optical or electrochemical sensors. This change can, for example, as already mentioned, be a coloration or the emission of luminescent radiation. These types of analyzers are known, for example, from DE 10 2011 005957 A1 and DE 10 2014 102600 A1. With these devices a fully automated determination of the measured values of relevant measurands is possible. The analysis of the measurement data and the calculation of the current measured values are thereby much less complex than the preparation and application of chemometric models as used in spectrometric in-line measuring devices. Furthermore, in comparison with the aforementioned in-line measurement methods, significantly lower detection/determination limits with a higher degree of accuracy can be selectively achieved, that is, even in the presence of interferents.
However, a disadvantage of these types of analyzer is the long measurement duration or low measuring frequency required due to taking and pretreating samples.